Grand Rounds

How Common is Noonan Syndrome When the NT is Large but Chromosomes Appear Normal?

BACKGROUND AND PURPOSE:

Noonan syndrome is an autosomal dominant disorder that occurs in approximately 1 in 1,000 to 2,500 people
It is the most common single gene disorder seen with NT and a well-known finding in association with cystic hygroma
Ali et al. (Prenatal Diagnosis, 2017) sought to determine the prevalence of Noonan syndrome in fetuses with increased nuchal translucency (NT) thickness in the first trimester of pregnancy

Retrospective cohort study
Centers all with AIUM certified prenatal diagnostic units, and NTQR certified teams
Inclusion criteria
- First trimester NT measurement ≥ 3 mm
- Normal karyotype by either a CVS or an amniocentesis
- Prenatal molecular genetic testing for Noonan syndrome available
2 labs reported results
- Lab 1: 9 Noonan syndrome genes plus Costello and CFC syndromes
- Lab 2: 7 Noonan syndrome genes plus Costello and CFC syndromes
  - Two genes not screened were NRAS and RIT1, but only make up 5% of Noonan syndrome postnatally
- Costello and CFC (cardiofaciocutaneous) syndromes have overlapping features with Noonan syndrome
Positive report: Known pathogenic variants in any tested gene
Negative report: Variants of uncertain clinical significance or no variants

804 fetuses had NT measurement of ≥ 3 mm
- Median NT was 3.6 mm
302 (37.6%) had karyotyping by CVS or amnio
- 200 (66.2%) had normal results
No molecular testing in 161 fetuses with normal karyotype (mean NT thickness 4.3 mm)
39 fetuses with normal karyotype (median NT thickness of 4.0 mm) were screened for Noonan syndrome
4 fetuses (10.3%) had variants consistent with this Noonan syndrome

Increased nuchal translucency (NT) is associated with a 10% risk of Noonan syndrome
Confirms previously reported literature (see Croonen et al; European Journal of Human Genetics, 2013)

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